rs387906485

Variant names:

• chrX-37783600-G-A
• rs387906485
• NM_000397.4:c.252G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-37783600-G-A
• chrX-37783600-G-C
• chrX-37783600-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_000397.4(CYBB):​c.252G>A​(p.Ala84Ala) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000917273: Several publications also reported experimental evidence evaluating an impact on protein function, demonstrating a residual NADPH oxidase activity and an abnormal neutrophil oxidative burst (e.g. Rae 1998, Gutierrez 2012)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A84A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CYBB NM_000397.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.49
• Publications: 17 publications found

Genes affected

CYBB (HGNC:2578): (cytochrome b-245 beta chain) Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes. CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole. [provided by RefSeq, Jul 2008]

CYBB Gene-Disease associations (from GenCC):

• granulomatous disease, chronic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency

  Inheritance: XL, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000917273: Several publications also reported experimental evidence evaluating an impact on protein function, demonstrating a residual NADPH oxidase activity and an abnormal neutrophil oxidative burst (e.g. Rae 1998, Gutierrez 2012).; SCV000564921: Published functional studies demonstrate that the variant results in the skipping of exon 3 and a minor fraction of mRNA expression (Ishibashi et al., 2001; Khaldi et al., 2009; Hui et al., 1996); PMID: 19483051, 25525159, 22929960, 10914676, 9585602, 8916969, 8900212, 32712647, 18546332, 33717137, 35140711, 22015033, 11435314, 8634410, 17543165, 15577746, 29560547, 23193493, 33325540, 30470980, 32084423, 31375816, 35874699, 34206017, 34175765
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-37783600-G-A is Pathogenic according to our data. Variant chrX-37783600-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000397.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBB	NM_000397.4	MANE Select	c.252G>A	p.Ala84Ala	splice_region synonymous	Exon 3 of 13	NP_000388.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBB	ENST00000378588.5	TSL:1 MANE Select	c.252G>A	p.Ala84Ala	splice_region synonymous	Exon 3 of 13	ENSP00000367851.4	P04839
	ENSG00000250349	ENST00000465127.1	TSL:5	c.171+357600G>A		intron	N/A	ENSP00000417050.1	B4E171
	CYBB	ENST00000968558.1		c.252G>A	p.Ala84Ala	splice_region synonymous	Exon 3 of 14	ENSP00000638617.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1046026 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 318182

African (AFR) AF: 0.00 AC: 0 AN: 25424

American (AMR) AF: 0.00 AC: 0 AN: 35099

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19050

East Asian (EAS) AF: 0.00 AC: 0 AN: 30025

South Asian (SAS) AF: 0.00 AC: 0 AN: 52913

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3988

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 794628

Other (OTH) AF: 0.00 AC: 0 AN: 44425

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Granulomatous disease, chronic, X-linked (3)
3	-	-	not provided (3)
1	-	-	Granulomatous disease, chronic, X-linked;C1970859:X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.98
PhyloP100		7.5
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.77		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387906485; hg19: chrX-37642853;